EP0888320A1 - Nouveaux n-aminoalkyl-2-anthracenecarboxamides; nouveaux ligands specifiques de sous-type de recepteur de dopamine - Google Patents

Nouveaux n-aminoalkyl-2-anthracenecarboxamides; nouveaux ligands specifiques de sous-type de recepteur de dopamine

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Publication number
EP0888320A1
EP0888320A1 EP97916093A EP97916093A EP0888320A1 EP 0888320 A1 EP0888320 A1 EP 0888320A1 EP 97916093 A EP97916093 A EP 97916093A EP 97916093 A EP97916093 A EP 97916093A EP 0888320 A1 EP0888320 A1 EP 0888320A1
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EP
European Patent Office
Prior art keywords
alkyl
compound according
naphthyl
compounds
piperazinyljbutyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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EP97916093A
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German (de)
English (en)
Inventor
Jun Yuan
Xi Chen
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Neurogen Corp
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Neurogen Corp
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Publication date
Application filed by Neurogen Corp filed Critical Neurogen Corp
Publication of EP0888320A1 publication Critical patent/EP0888320A1/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • This invention relates to anthracenecarboxamide derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to N-Aminoalkyl-2-anthracene- carboxamides and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment or prevention of various neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
  • neuroleptics The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors.
  • neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain.
  • EPS extrapyramidal side effects
  • tardive dyskinesias which are attributed to blockade of D2 receptors in the striatal region of the brain.
  • D3 receptor subtype has recently been identified (Sokoloff et al., Nature, 242: 146 (1990). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D3 receptor may play a major role in the etiology of schizophrenia.
  • Selective D3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
  • Compounds of the present invention demonstrate high affinity and selectivity in binding to the D3 receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D3 receptors.
  • United States Patent 5,395,835 discloses N-aminoalkyl-2-napthalamides which have affinity at dopamine D3 receptors.
  • the compounds of the present invention differ significantly from this prior art in that they possess an anthracenecarboxamide substructure.
  • This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.
  • the invention provides compounds of general Formula I useful in the treatment and/or prevention of various neuropsychological disorders.
  • the invention also provides pharmaceutical compositions comprising compounds of Formula 1.
  • the invention further relates to the use of such compounds and compositions in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia.
  • affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia.
  • Compounds of this invention are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
  • the compounds of the present invention are useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
  • dopamine D 3 receptors are concentrated in the limbic system (Taubes, Science, 265: 1034 (1994)) which controls cognition and emotion
  • compounds which interact with these receptors also have utility in the treatment of cognitive disorders.
  • Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia.
  • Other disorders involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention that interact specifically with the dopamine D 3 receptor subtype.
  • compounds of this invention may be useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D3 receptors which selectively exist in limbic area known to control emotion and cognitive functions.
  • the compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse (Caine and Koob, Science, 260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al., Clin. Psychopharmacol., 7: 35 (1992)).
  • substance abuse Caine and Koob, Science, 260: 1814 (1993)
  • obsessive compulsive disorder Goodman et al., Clin. Psychopharmacol., 7: 35 (1992)
  • the interaction of the compounds of the invention with dopamine receptor subtypes is demonstrated below. This interaction results in the pharmacological activities of these compounds.
  • R 1 -R9 are the same or different and represent hydrogen, C ⁇ -C 6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C)-C 6 alkoxy, -O 2 CR', -NHCOR', -COR',
  • R' is C ⁇ -C 6 alkyl and wherein m is 0, 1 or 2; or R 1 -R9 independently represent -CONR'R", or -NR'R" where R' and R" independently represent hydrogen or C
  • the invention relates to the use of compounds of formula I in the treatment and/or prevention of neuropsychochological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.
  • neuropsychochological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.
  • Ri-Rio are as defined above; and R represents an aminoalkyl group of the formula
  • A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms;
  • Z is N or C;
  • Rl i and R12 are the same or different and represent hydrogen or Ci-C ⁇ alkyl; or Rl i and Rj2 together with the the 6-membered ring to which they are attached form a 5 to 8-membered ring; and W is phenyl, naphthyl, l-(5,6,7,8-tetrahydro)naphthyl or 4-(l,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, -C ⁇ alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
  • Preferred compounds of formula I A include those where R1-R9
  • R 1 -R 12 are as defined above;
  • A, Z and W are as defined above.
  • the present invention further encompasses compounds of Formula II:
  • R1-R12, A, and W are as defined above.
  • Preferred compounds of formula II are those where R1-R9 are hydrogen; A is C3-C5 alkylene; and W is naphthyl or phenyl optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromefhyl or trifluoromethoxy.
  • More preferred compounds of formula II are those where R1-R 0 are hydrogen; A is C3-C5 alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the piperazine ring), the groups being independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.
  • Particularly preferred compounds of formula II are those where R1-R10 are hydrogen; A is C4 alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the piperazine ring), the groups being independently selected from chloro, methyl, and methoxy.
  • the present invention further encompasses compounds of Formula III:
  • R1-R12, A, and W are as defined above.
  • Preferred compounds of formula III are those where Rj-Rio are hydrogen; A is C3-C5 alkylene, more preferably butylene; and W is naphthyl or phenyl optionally substituted with up to three groups independently selected from halogen, -C6 alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
  • Particularly preferred compounds of formula III are those where R1-R10 are hydrogen; A is C3-C5 alkylene, more preferably butylene; and W is phenyl or naphthyl.
  • the invention also provides compounds of Formula IV
  • RlO is hydrogen or C1-C4 alkyl
  • A represents alkylene group of 2 to 6 carbon atoms; Z is nitrogen or carbon;
  • W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1 -C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
  • Preferred compounds of formula IV are those where Rio is hydrogen and A is C3-C5 alkylene. More preferred compounds of formula IV are those where Rio is hydrogen; A is C4 alkylene; Z is nitrogen; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring), the groups being independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.
  • the invention also provides compounds of Formula V
  • RlO is hydrogen or C1-C4 alkyl
  • A represents alkylene group of 2 to 6 carbon atoms
  • W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
  • Preferred compounds of formula V are those where Rio is hydrogen and A is C3-C5 alkylene. More preferred compounds of formula V are those where Rio is hydrogen; A is C4 alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 positions and/or 6 positions (relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring), the groups being independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.
  • the invention also provides compounds of Formula VI
  • RlO is hydrogen or C1-C4 alkyl
  • A represents alkylene group of 2 to 6 carbon atoms
  • W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C1-C6 alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
  • Preferred compounds of formula VI are those where Rio is hydrogen and A is C3-C5 alkylene. More preferred compounds of formula VI are those where Rio is hydrogen; A is C4 alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 positions and/or 6 positions (relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring), the groups being independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.
  • enantiomers When a compound of the invention is obtained as a mixture of enantiomers, these enantiomers may be separated, when desired, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
  • Representative compounds of the present invention which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts.
  • the present invention also encompasses prodrugs, e.g., acylated prodrugs, of the compounds of Formula I.
  • prodrugs e.g., acylated prodrugs
  • Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed by Formula I.
  • Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenes
  • alkyl and “lower alkyl” is meant straight and branched chain alkyl groups having from 1-6 carbon atoms, e.g., C1-C alkyl.
  • lower alkoxy and “alkoxy” is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms, e.g., C1-C6 alkoxy.
  • halogen is meant fluorine, chlorine, bromine and iodine.
  • amino portion of the aminoalkyl group represented by R above includes groups represented by the formula Q
  • Th formula Q represents saturated heterocyclic ring systems such as, for example, piperidinyl and piperazinyl, as well as unsaturated heterocyclic ring systems such as, for example, 1, 2, 3, 6- tetrahydropyrindine.
  • Preferred Q groups are the following:
  • W groups of the invention are phenyl optionally substituted with up to two substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy. These optional phenyl substituents are preferably in the 2 and/or 3 and/or 6 positions of the phenyl group relative to the point of attachment of the phenyl group to the 6-membered nitrogen containing ring.
  • N-Aminoalkylanthracenecarboxamides are shown in Table 1 below. The number below each compound is its compound number. Each of these compounds may be prepared according to the general reaction Scheme I set forth below.
  • Particular compounds according to the invention include:
  • the invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders.
  • the pharmaceutical utility of compounds of this invention are indicated by the following assays for dopamine receptor subtype affinity.
  • Pellets of COS cells containing recombinantly produced D2 or D3 receptors from African Green monkey were used for the assays.
  • the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C and pH 7.4.
  • the sample is then centrifuged at 30,000 x g and resuspended and rehomogenized.
  • the sample is then centrifuged as described and the final tissue sample is frozen until use.
  • the tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl. Incubations are carried out at 48°C and contain 0.4 ml of tissue sample, 0.5 nM ⁇ H-YM
  • Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding.
  • the binding characteristics of representative compounds of the invention for D2 and D3 receptor subtypes are shown in Table 2 for rat striatal homogenates.
  • Compound numbers relate to compounds shown above in Table 1.
  • the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxyme hylcellulose, methylcellulose, hydropropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the and partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg ofan active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • Formula VII wherein Rj, R2, R3, R4, R5, 6> R7 > R8> R9, RlO, l 1 , Rl2 > A , Z and W are as defined above for Formula IA.
  • a compound of Formula VII may be activated by l,l'-carbonyldiimidazole (CDI) or thionyl chloride (SOC12) or the like in solvents such as tetrahydrofuran or dichloromethane at room temperature.
  • CDI l,l'-carbonyldiimidazole
  • SOC12 thionyl chloride
  • the resulting activated species may be subsequently reacted with the required compound of Formula VIII to afford a compound of Formula I as the desired product.
  • the compounds of Formula VII may be prepared by literature procedures or procedures analogous to those described in literature.
  • the compounds of Formula VIII are either known or capable of being prepared by various methods known in the art.
  • the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.
  • protection of certain reactive functionalities may be necessary to achieve some of the above transformations.
  • the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups.
  • the organic layer is washed with aqueous Na2CO3, dried (Na2SO4) and concentrate in vacuo to give the title compound (183 mg, 80%).
  • the hydrochloride salt is prepared by treating th free base with ethyl acetate-HCl.
  • the hydrochloride salt of the title compound has a melting point o 245-247 °C.

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Abstract

L'invention porte sur des composés répondant à la formule (I) ou à leurs sels d'addition d'acide, acceptables du point de vue pharmaceutique. Dans cette formule, R1, R2, R3, R4, R5, R6, R7, R8 et R9 sont identiques ou différents et représentent un hydrogène, un alkyle en C1-C6, un halogène, un hydroxy, un amino, un cyano, un nitro, un trifluorométhyle, un trifluorométhoxy, un alkoxy en C1-C6, -O2CR', -NHCOR', -COR', -SOmR', R' représentant un alkyle en C1-C6, et m valant 0, 1 ou 2. R1, R2, R3, R4, R5, R6, R7, R8 et R9 peuvent, également, représenter, indépendamment, -CONR'R'' ou -NR'R''; R' et R'' y représentant indépendamment un hydrogène ou un alkyle en C1-C6. Dans cette même formule, R10 représente un hydrogène ou un alkyle en C1-C6 et R représente un groupe aminoalkyle. Ces composés s'avèrent utiles dans le traitement de troubles de l'affectivité, comme la schizophrénie, la dépression et la maladie d'Alzheimer, de troubles de la motricité comme le parkinsonisme et la dystonie, ainsi que d'autres troubles découlant d'un blocage dopaminergique, la pharmacodépendance et des troubles obsessionnels de type compulsionnel, par exemple. Les composés selon l'invention sont, de surcroît, efficaces s'agissant de traiter des effets secondaires extrapyramidaux liés à l'emploi d'agents neuroleptiques classiques.
EP97916093A 1996-03-21 1997-03-20 Nouveaux n-aminoalkyl-2-anthracenecarboxamides; nouveaux ligands specifiques de sous-type de recepteur de dopamine Ceased EP0888320A1 (fr)

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US08/619,351 US5703235A (en) 1996-03-21 1996-03-21 N-Aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
US619351 1996-03-21
PCT/US1997/004418 WO1997034884A1 (fr) 1996-03-21 1997-03-20 Nouveaux n-aminoalkyl-2-anthracenecarboxamides; nouveaux ligands specifiques de sous-type de recepteur de dopamine

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US5703235A (en) 1996-03-21 1997-12-30 Neurogen Corporation N-Aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
US5763609A (en) * 1996-03-21 1998-06-09 Neurogen Corporation Certain pyrrolo pyridine-3-carboxamides; a new class of gaba brain receptor ligands
AU6230698A (en) * 1997-02-26 1998-09-18 Sumitomo Pharmaceuticals Company, Limited Dopamine d4 receptor antagonist
IL157412A0 (en) * 2001-02-16 2004-03-28 Aventis Pharmaceuticals Inc Av Novel heterocyclic amide derivatives and their use as dopamine d3 receptor ligands
ATE348099T1 (de) * 2001-02-16 2007-01-15 Aventis Pharma Inc Heterocyclische harnstoffderivate und deren verwendung als dopamine d3 receptor liganden

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US4888353A (en) * 1986-02-28 1989-12-19 Erbamont, Inc. Carboxamides useful as antiemetic or antipsychotic agents
US4863921A (en) * 1988-04-27 1989-09-05 Rorer Pharmaceutical Corporation Dibenzofurancarboxamides and their pharmaceutical compositions and methods
US5254552A (en) * 1988-05-24 1993-10-19 American Home Products Corporation Aryl-and heteroaryl piperazinyl carboxamides having central nervous system activity
US4935511A (en) * 1989-09-26 1990-06-19 Rorer Pharmaceutical Corporation Benzoxazine and benzoxazepine carboxamide 5-HT3 antagonists
FR2682953B1 (fr) * 1991-10-23 1995-04-21 Inst Nat Sante Rech Med Nouveaux derives de naphtamides, leur procede de preparation et leur application dans le domaine therapeutique.
SE9201138D0 (sv) * 1992-04-09 1992-04-09 Astra Ab Novel phthalimidoalkylpiperazines
US5395835A (en) * 1994-03-24 1995-03-07 Warner-Lambert Company Naphthalamides as central nervous system agents
US5703235A (en) 1996-03-21 1997-12-30 Neurogen Corporation N-Aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands

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WO1997034884A1 (fr) 1997-09-25
US6239179B1 (en) 2001-05-29
AU2335797A (en) 1997-10-10
US5703235A (en) 1997-12-30
JPH11507064A (ja) 1999-06-22
US5883257A (en) 1999-03-16
CA2249555A1 (fr) 1997-09-25
JP3038018B2 (ja) 2000-05-08
US6025493A (en) 2000-02-15

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